Hyperlipidemia refers to high blood cholesterol levels and is asymptomatic. However, hyperlipidemia is a very significant condition, because it causes angina pectoris, myocardial infarction and arteriosclerosis. Statins, drugs that are commonly used to treat hyperlipidemia, exhibit therapeutic effects mainly by lowering LDL-C, but their effects on the prevention of cardiovascular diseases are still very insufficient. A recent study reported that elevated concentration of high-density lipoprotein (HDL-C) is very effective in preventing cardiovascular diseases as effective as lower low-density lipoprotein cholesterol (LDL-C) (Goldbourt et al, Arterioscler Thromb Vasc Biol, 1997, 17, 107-113). Among drugs that are used to increase HDL-C, the most effective drug is Niacin. However, this drug needs to be taken in relatively large doses and causes side effects such as facial flushing (Taylor et al, Circulation, 2004, 110, 3512-3517).
Meanwhile, cholesterol ester transfer protein (CETP) is a protein that participates in reverse cholesterol transport (the reverse transport of cholesterol from peripheral tissue to the liver). When CETP is inhibited, HDL-C can be effectively increased, thus preventing cardiovascular diseases. Accordingly, the development of compounds capable of inhibiting CETP activity is very important (Barter et al., Arterioscler Thromb Vasc Biol, 2003, 23, 160-167).
CETP inhibitors known to date can be divided according to structure into Torcetrapib (WO 02/088085) and Anacetrapib (WO 2006/014357), which are 3,5-bis-trifluoromethyl-benzene derivatives, and Dalcetrapib (WO 98/35937) which is a benzenethiol derivative.
However, among these CETP inhibitors, Torcetrapib causes a increases in blood pressure and an increase in mortality, and thus clinical trials thereof were terminated. It was reported that such side effects occur because Torcetrapib increases the levels of hormones, such as aldosterone and cortisol, associated with a significant elevation in blood pressure, and increases the thickness of the vascular wall to cause inflammation, thus increasing mortality (Ferrest et al, British Journal of Pharmacology, (2008) 154, 1465-1473). The other CETP inhibitor Dalcetrapib has not been reported to cause such side effects, but is known to have insufficient rise in HDL-C (Hisashi Shinkai. Expert Opinion on Therapeutic Patents, 2009, 19(9), 1229-1237). Among such CETP inhibitors, Anacetrapib and Dalcetrapib are in clinical trials for the purpose of treating hyperlipidemia and cardiovascular diseases by increasing HDL-C and decreasing LDL-C(Niesor et al, Journal of lipid Research, 2010, 51, 3443-3453).